The progress in studies on O-superfamily conotoxins

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1 Chinese Bulletin of Life Sciences Vol. 17, No. 5 Oct., (2005) O- ( ) O- δ- µο- ω- κ- 24~33 ICK Q71 R966.3 A The progress in studies on O-superfamily conotoxins ZHANG Wei 1 *, HAN Yu-Hong 1,2 (1 Institute of Protein Research, Tongji University, Shanghai , China; 2 Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of CAS, Shanghai , China) Abstract: O-superfamily is one of the most complex group among conotoxins, it is composed of several members such as δ, µο-, ω, κ-contoxins. Usually, O-superfamily conotoxins contain 24~33 amino acid residues with three disulfide bonds. This disulfide-rich peptides can potently and selectively interfere with voltage-gated cation channels. This article reviews their characteristics of biochemistry, molecular genetics, physiology and pharmacology, relationship between structure and function, and application perspective as well. Key words: ion channel disulfide bond conotoxins (conotoxin, CTx) (conus) 10~ ( ) (1982 ) * (1977 )

2 O- 405 ( 1) (contulakin) (conantokin) (conopressin) [1] O- δ- µο- ω- κ- δ-ctx Na + µο-ctx Na + ω-ctx Ca 2+ κ-ctx K + [2] 1 O- - δ- µο- ω- κ- 24~33 4 Loop Cys I -Cys IV Cys II -Cys V Cys III -Cys VI δ-ctx µο-ctx ω-ctx 4~6 C N Cys mrna O- (Pre ) (Pro ) (mature ) O- cdna Pro κ-ctx ω-ctx δ-ctx µo-ctx κ-pviia ω-gvia N ( 1) C. purpurascens κ-pviia δ-pvia ω-ctx K + κ-ctx Ca 2+ ω-ctx δ-pvia µο- MrVIB O- K + Ca 2+ (κ-ctx ω-ctx); Na + (δ-ctx µο-ctx 2 O- 2.1 δ- 25~33 4 Loop Na + 1 O C-C-CC-C-C δ Na + C-C-CC-C-C µο Na + C-C-CC-C-C ω Ca 2+ C-C-CC-C-C κ K + M CC-C-C-CC µ Na + CC-C-C-CC ψ nach CC-C-C-CC κμ K + A CC-C-C α nach CC-C-C-C-C αα nach CC-C-C-C-C κα K + S C-C-C-C-C-C-C-C-C-C σ 5-HT 3 T CC-CC τ? CC-CC χ? P C-C-C-C-C-C spastics? I C-C-CC-CC-C-C K + C-C conopressin C-C contryphan? C-C contulakin C-C conantokin NMDA C-C conorfamide Rfamide

3 406 1 O- δ F9 I12 L16 ( 2) Ala [3] C. purpurascens δ-pvia δ-ctx (the lock jaw syndrome) [4] δ-pvia Na V 1.2 Na + [5] δ-pvia Na V 1.4 Na V 1.6 [6] C.gloriamaris δ-gmvia Na + [7] Na V 1.2 Na V 1.4 Na V 1.6 C. textile δ-txvia Na + [3,8~9] Na + [9] (silent binding) δ-pvia δ-txvia Na + δ-ctx δ-ctx Na + Na + Na + Na + δ-ctx Site VI Na + [10] δ-evia Na + Na + [11] Na + (rna V 1.2 rna V 1.3 rna V 1.6) (rna V 1.4) (hna V 1.5) Na + δ-evia 2 δ- δ- C. purpurascens PVIA EACYAOGTFCGIKOGLCCSEFCLPGVCFG* C. nigropunctatus NgVIA SKCFSOGTFCGIKOGLCCSVRCFSLFCISFE C. striatus SVIE DGCSSGGTFCGIHOGLCCSEFCFLWCTFID C.catus CVIE YGCSNAGAFCGIHOGLCCSELCLVWCT C. consors CnVIA YECYSTGTFCGINGGLCCSNLCLFFVCLTFS C. ermineu EVIA DDCIKOYGFCSLPILKNGLCCSGACVGVCADL C. textile TxVIA WCKQSGEMCNLLDQNCCDGYCIVLVCT C. gloriamaris GmVIA VKPCRKEGQLCDPIFQNCCRGWNCVLFCV * C O

4 O- 407 Na + Na µo- µο- CTx µο-ctx µ-ctx Na + µο-ctx δ-ctx ω-ctx ICK µ-ctx α-β CSαβ µο-ctx µ-ctx M µο-mrvia µο-mrvib δ-ctx ω-ctx δ-ctx Na + ω-ctx Ca 2+ µ-ctx Site I ω-ctx Site I [12] µο-ctx µ-ctx Na + [13] µο-mrvia µ-giiib (>10 nmol) µο-mrvia µ-giiib µο-mrvia µ-giiib µο-mrvia Na + Na + µο-mrvia µο-mrvib Na + Ca 2+ [14] µο-mrvia µο-mrvib ( 3 ) ( 3) Ca 2+ µο-mrvia Ca 2+ µο-mrvib Ca 2+ Ca ω- ω-ctx Ca 2+ Ca 2+ L N P Q R T L Ca 2+ Ca V 1 P/Q N R Ca 2+ Ca V 2 T Ca 2+ Ca V 3 ω-ctx Ca 2+ ω-mviia N Ca 2+ (Ca V 2.2) ω-mviic P/Q Ca 2+ (Ca V 2.1) [15~16] ω-gvia N Ca 2+ ω-cvia N Ca 2+ ω-cvib ω-cvic N P/Q Ca 2+ ω-cvid N Ca 2+ P/Q Ca 2+ [17] N Ca 2+ ω-cnviia Loop4 (SSSKGR) Ca 2+ ω-cnviia N Ca 2+ ω-gvia [18] C.pennaceus ω-pnvia ω-ctx ( 4) DHP (dihydropyridine) Ca 2+ [19] C. textile ω-txviidhp L- Ca 2+ CTx [20] 2.4 κ- 80 ( K V 1.X K V 2.X ) S1~S6 α C. purpurascens κ-pviia [21] κ-pviia K + Shaker K + K + K V 1.1 Shaker K V 1.1 κ-pviia S5~S6 κ- PVIIA Charybdotoxin Shaker K + Shaker K + S5~S6 3 µο- µο- C.marmoreus µο-mrvia ACRKKWEYCIVPIIGFIYCCPGLICGPFVCV C.marmoreus mo-mrvib ACSKKWEYCIVPILGFVYCCPGLICGPFVCV

5 408 4 ω- ω- C. geographus GVIA CKSOGSSCSOTSYNCCR-SCNOYTKRCY* C. magus MVIIA CKGKGAKCSRLMYDCCTGSC-R-SGKC* C. magus MVIIC CKGKGAPCRKTMYDCCSGSCGR-RGKC* C. striatus SVIA CRSSGSOCGVTSI-CC-GRCYR--GKCT* C. catus CVIA CKSTGASCRRTSYDCCTGSCRS--GRC* C. catus CVIB CKGKGASCRKTMYDCCRGSCRS--GRC* C. catus CVIC CKGKGQSCRKLMYDCCTGSCSRR-GKC* C. catus CVID CKSKGAKCSKLMYDCCSGSCSGTVGRC* C. consors CnVIIA CKGKGAOCTRLMYDCCHGSCSSSKGRC* C. textile TxVII CKQADEPCDVFSLDCCTGICLG-V--CMW C. pennaceus PnVIA GCLEVDYFCGIPFANNGLCCSGNCVFVCTPQ * C O (microsite) F424 G Charybdotoxin 3 κ-pviia κ-pviia C. purpurascens Na + δ-pvia 3 O- O-9 ω-gvia [22] ω-mviia [23] ω-mviic [24] ω-mviid [25] ω-svib [26] ω-txvii [27] ω-cvid [17] δ-txvia [28] κ-pviia [29] β (β1 β2 β3) (inhibitor cysteine knot motif, ICK motif) [30] Cys I -Cys IV Cys II -Cys V Cys III -Cys VI O- Loop Loop Loop2 Loop4 Nielson [31] ω-mviia ω-mviic Loop1 Loop3 Loop2 Loop4 N P/Q Ca 2+ O- Loop2 Loop4 δ-evia Loop2 O- Ser 11-Leu 19 Loop4 3 ( 2) 2 3 γ- Loop2 Pro13 Pro13 Ala P13Aδ-EVIA δ-evia 50% ω-gvia ω-mviia Try13 Ala Na % Lys2 Ala 97.5% Try13 Lys2 Na + δ-txvia ω-gvia ω-mviia δ-txvia δ-txvia 3 2 ω-gvia ω-mviia δ-txvia δ-txvia Na + ω-txvii δ-txvia ω-txvii (Ala 4 Met 25 Trp 26) δ-txvia ω-txvii δ-txviaω-cvid HNMR Loop2 Loop4 Loop4 Loop2 GVIA MVIIA κ-pviia Shaker K + κ-pviia Shaker P-Loop Ala K + P-Loop κ-pviia K + Savarin [29] κ-

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